MicroRNA-381 suppresses the proliferation of osteosarcoma cells through LRH-1/Wnt/β-catenin signaling pathway

Abstract

We explored the function of microRNA-381 on osteosarcoma cell growth and anticancer mechanism for clinic treatment. MicroRNA-381 of osteosarcoma patients was decreased, microRNA-381 levels were more downregulated at stages III/IV than those at stage I/II in osteosarcoma patients. Downregulation of microRNA-381 using anti-microRNA-381 mimics increased cell proliferation, decreased LDH activity and apoptosis, and inhibited caspase‑3/9 activities, Bax/Bcl-2 and p53 protein expression in vitro osteosarcoma cells through upregulation of LRH-1/Wnt/β-catenin signaling pathway. Overexpression of microRNA-381 using microRNA-381 mimics inhibited cell proliferation, induced apoptosis and increased LDH activity, caspase‑3/9 activities, expression of Bax/Bcl-2 and p53 protein in osteosarcoma of in vitro model through downregulation of LRH-1/Wnt/β-catenin signaling pathway. Si‑LRH‑1 promoted the anticancer effects of microRNA-381 on osteosarcoma cell growth through Wnt/β‑catenin signaling pathway. Thus, our data suggested that microRNA-381 suppresses the proliferation of osteosarcoma cells through upregulation of LRH-1/Wnt/β-catenin signaling pathway.

Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

“…To begin with, increasing evidence suggests that LRH-1 induces the expression of antiapoptotic proteins, such as Bcl-xL and Bcl-2. 64,103 Concurrently, it seems to inhibit caspase activity and transcriptionally repress pro-apoptotic factors, such as Bax and p53. 64 LRH-1 thus likely contributes to stress, respectively, cell death resistance and survival of malignant cells by directly counteracting mitochondrial apoptosis signaling.…”

“…Studying the role of microRNA‐381 in osteosarcoma cells, they were able to show that the LRH‐1/WNT/beta‐catenin signaling axis controls proliferation, but also prevents apoptosis in this type of cancer by inhibition of caspase 3 and 9 activities, while simultaneously positively regulating Bcl‐2 expression. Additionally, upregulation of the LRH‐1/WNT/beta‐catenin pathway reduced p53 and Bax expression further contributing to cellular viability 64 . Interestingly, an inverse correlation between microRNA‐381 and LRH‐1 expression was also observed in HCC.…”

“…Additionally, upregulation of the LRH-1/WNT/ beta-catenin pathway reduced p53 and Bax expression further contributing to cellular viability. 64 Interestingly, an inverse correlation between microRNA-381 and LRH-1 expression was also observed in HCC. Also in this context, targeting LRH-1 by microRNA-381 reduced LRH-1-mediated WNT/beta-catenin signaling.…”

“…60,61 Similar correlations were, however, also established in cancers where only little is known about the contribution of LRH-1, such as hepatocellular carcinoma (HCC), 62 nonsmall cell lung cancer (NSCLC) 63 and osteosarcoma. 64 With a particular focus on proliferation, evidence for the rather well studied role of LRH-1 in human pancreatic, breast and intestinal cancers will be reviewed in the following.…”

An Insight into the Roles of MicroRNAs and Exosomes in Sarcoma

“…Individuals with LFS are known to have a high risk of developing osteosarcoma [90]. miR-381 and miR-373 affect p53 regulation via Wnt and PI3K/AKT signaling [76,77]. miR-1281 is upregulated by endoplasmic reticulum (ER) stress.…”